Despite the presence of HIV-1 in the oral cavity, transmission of the virus through saliva is rare, which implicates innate/natural antiviral mechanisms for suppressing transmission. Such endogenous antiviral molecules, including secretory leukocyte protease inhibitor (SLPI) and thrombospondin (TSP-1) inhibit HIV-1 infection of mononuclear cells during or soon after internalization. To further clarify the antiviral functions of SLPI as well as its role in innate host defense, a multifaceted approach has revealed that in addition to antiproteolytic activity, SLPI inhibits the transcription factor NF-kappa B to block monocyte/macrophage cytokine and chemokine synthesis. Generation of mice homozygous for a null mutation of SLPI have provided insight into its patterns of expression, function and regulation. In additional studies focusing on the regulation of HIV production after infection, opportunistic pathogens and immune activation were shown to influence viral replication. For example, Mycobacterium avium promotes HIV infection by activating the NF-kappa B pathway to stimulate cytokine and chemokine production and HIV co-receptor (CCR5) expression, while inhibiting apoptosis. This results in accumulation of susceptible viral host cells which favors viral replication. In tonsils and in sites of mucosal inflammation, the dynamic relationship between lymphocytes, macrophages and high levels of HIV emphasizes that immune activation contributes to viral progression and suggests interventional approaches.